1-phenylalkanecarboxylic acid derivatives as anticonvulsant and neuroprotective agents

ABSTRACT

The compounds belong to the class of non-narcotic, non-opiate derivatives  the 1-phenylalkanecarboxylic acid basic structure useful as anticonvulsant and neuroprotective agents. The compounds include novel derivatives as well as previously published species. Methods for controlling convulsions in a variety of pharmaceutical formulations and modalities are also provided.

FIELD OF THE INVENTION

This invention pertains to a group of compounds which exhibit surprisinganticonvulsant and neuroprotective properties, and methods for their usein controlling seizures or convulsions. The compounds are1-phenylalkanecarboxylic acid derivatives. The invention is alsodirected to pharmacological methods of their use as effectiveanticonvulsant and neuroprotective agents.

BACKGROUND OF THE INVENTION

One of the challenges of the science of neurological pharmacology is thecontrol of different types of convulsions (as characterized by theclinical manifestations of the attacks and by specific patterns in theelectroencephalogram (EEG)) with pharmaceutical agents. The challenge isheightened by the fact that many anticonvulsant compositions known tothe art of pharmacy introduce toxic side effects to patients beingadministered treatments containing them. A noteworthy example is theimpairment of the clinical efficacy of valproic acid for treatingsymptoms of childhood and adolescent epilepsy by potentialembryotoxicity and hepatotoxicity. Pharmaceutical compounds whichpotentiate (i.e. enhance the potency of) anticonvulsant drugs have beendeveloped and introduced into the field to help meet this heightenedchallenge. Relatively few compounds are known which have stand-aloneconvulsion control properties. There is a need for compounds havinginherent ability to control seizures or convulsions as well asconcurrent properties of potentiating other anticonvulsant drugs withoutintroducing toxic side effects to patients requiring this treatment. Itis also highly desirable for an anticonvulsant or neuroprotective agentto be effective against a wide a range of convulsion types. Drugs withdifferent treatment and potentiating profiles enable pharmaceutical andmedical practitioners to reach a wider range of patients requiringtreatment with greater flexibility and lower risk of harm or discomfortthrough unavoidable side effects. The present invention in its variousaspects helps meet the needs of this challenging field.

Carbetapentane [1-phenylcyclopentanecarboxylic acid2-(2-diethylaminoethoxy)ethyl ester] has the following structuralformula: ##STR1##

This compound belongs to a class of compounds that may be characterizedas non-narcotic, non-opiate antitussives, which is a fairly broad classof compounds that are believed to bind to specific sites in the centralnervous system (U.S. Pat. No. 4,694,010). Many compounds which fallwithin this class are available from commercial sources or may besynthesized using well known techniques. The cough suppressant propertyof carbetapentane, or antitussive compositions containing it, has beendisclosed in U.S. Pat. Nos. 4,694,010; 4,898,860; 4,892,877; and4,906,638.

It has been shown that some non-narcotic, nonopiate antitussives enhancethe potency of some anticonvulsant drugs. This effect, often called"potentiation" is manifested by the lowering of the median effectivedose (ED₅₀) of anticonvulsant drugs which are coadministered with apotency enhancing agent. Initial studies in this particular field wereconducted to test the diphenylhydantoin potentiating properties ofdextromethorphan (D-3-methoxy-N-methylmorphinan), a member of the classof unnatural, non-narcotic opioid enantiomers [(+)-morphinans], see U.S.Pat. No. 4,694,010; Mol. Pharmacol. 23:619-628 and 23:629-640 (1983);and Brain Res. 383:314 (1986). The practical effect of the discoverythat non-narcotic compounds such as carbetapentane, caramiphen,dextromethorphan and others would enhance the potency of powerfulanticonvulsant agents was that the maintenance dosages of theanticonvulsant agents, which characteristically have toxic side effects,could be reduced and rendered safer. Carbetapentane potentiates someanti-convulsant compounds, such as diphenylhydantoin (phenytoin), andother anti-epileptic hydantoins. In addition, carbetapentane has someanticonvulsant activity independent of its potentiating properties. Somecompounds which can be derived from the basic phenylalkanecarboxylicacid structure have been suggested as potential spasmolytic agents(British Patent No. 753,779). The present invention provides compoundswith surprising anticonvulsant and nuroprotective properties, andpharmacological methods for using them without dependence, behavioralmodification, toxicity, undesirable side effects, or other liabilitiesthat characterize many prior art compounds and treatment modalities.

SUMMARY OF THE INVENTION

It has been discovered that some novel compounds as well as a previouslypublished species derived from the phenylalkane carboxylic acid basicstructure have inherent anticonvulsant or neuroprotective properties.Compounds possessing these properties are provided in this invention.Accordingly, this invention is directed primarily to a group ofcompounds which have anticonvulsant and/or neuroprotective activity. Theinvention is also directed to methods for treating convulsive disordersusing compounds of the invention in a variety of pharmaceuticalpreparations and modalities.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a semilog plot of the doses at which a given anticonvulsantcompound controls convulsions in a corresponding percentage of thesubject animals tested.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have prepared a group of compounds including somenovel species and have discovered that the compounds surprisingly havepotent anticonvulsant and neuroprotective properties. A method fortreating convulsions and other neurological disorders exhibiting thesame or a closely similar biochemical pathway of symptomatology usingcompoundsof the invention has been developed in accordance with thesediscoveries.

The compounds of this invention are 1-phenylalkanecarboxylic acidderivatives which have anticonvulsant and/or neuroprotective propertiesasestablished by testing with laboratory animals. Preferred compounds ofthe invention are more potent than prior art compounds as showed bystandard laboratory testing described further below, and providetherapeutic treatment without the undesired side effects thatcharacterize some compounds of the prior art. The invention is alsodirected to methods of using the compounds in a variety of acceptablepharmaceutical formulations.

The compounds of the present invention have the following formula:##STR2##in which X is --C(═O)O--, --CH₂ --O--, --C(═O)NH, --CH₂ NH, or--CH₂ N(C₂ H₅); and n is an integer 1 through 5, inclusive, providedthat when X is --C(═O)O--, then n may not be 3.

An anticonvulsant or neuroprotective compound of this invention may beadministered alone or as part of a pharmaceutical formulation, and ineither case administration may be by any suitable route including oral,rectal, nasal, topical (including buccal and sublingual), and parenteral(including subcutaneous, intramuscular, intravenous and intradermal)with oral or parenteral being preferred. It will be appreciated that thepreferred route may vary with, for example, the condition and age of therecipient or the type, nature, and severity of the convulsion. Apreferreddose is in the range of 1 to 1,000 mg of a compound of theinvention as active ingredient, alone or in a pharmaceuticalformulation.

It is preferable to present the active anticonvulsant andneuroprotective compounds of this invention as part of a pharmaceuticalformulation. The formulations of this invention comprise at least oneadministered ingredient as defined above, together with one or moreacceptable carriers, flavorings or coatings where suitable, andoptionally other therapeutic agents. The carrier(s) must be acceptablein the sense that they must be compatible with the other ingredients ofthe formulation and they must not be harmful to the recipient.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods practiced in the art of pharmacy. Ingeneral, formulations are prepared by bringing the active ingredientsinto association with finely divided solid carriers, liquid carriers, orboth, and then, if necessary or desired, shaping the product.Formulations useful in the practice of the present invention which aresuitable for oral administration may be presented as discrete units suchas capsules, cachets, or tablets containing a predetermined amount ofthe active ingredient; as a powder or granules; or as a solution orsuspension in an aqueous or non-aqueous liquid. Preferred unit-dosageforms are liquid formulations for injection or oral administration, andtablets, lozenges, capsules or cachets, also suitable for oraladministration.

Compressed tablets may be prepared by compressing with suitable meansthe active ingredients in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, diluent,preservative, surface-active or dispersing agent. Molded tablets may beprepared with suitable molding means such as punching or compressing theactive ingredient and any binders or fillers in a tabletting machine. Amixture of the powdered compound moistened with an inert liquid diluentmay also be used. Tablets may be optionally coated or scored and may beformulated so as to provide slow or controlled release of the activeingredient contained in the tablet. Tablets may optionally contain otheringredients,such as additional therapeutic agents. Soft shell gelatincapsules used as pharmaceutical coatings are suitable for orallyadministered formulations of this invention, also.

Formulations suitable for topical administration include lozengescomprising the ingredients in a flavored medium, pastilles comprisingthe active ingredient in an inert medium such as gelatin or glycerin. Apreferred topical delivery system is a transdermal patch containing theingredient to be administered.

A suitable formulation for nasal administration may include a carriercomprising a solid, coarse powder having particulate size averaging 20to 500 microns in diameter. Such a formulation would be administered byrapidinhalation through the nasal passage, for example, from a containerof the powder held close to the nose. Suitable formulations including aliquid carrier might include aqueous or oily solutions of the activeingredient. A preferred system of delivery for nasal administration is anasal spray.

Suitable formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the recipient; and aqueous and non-aqueous sterilesuspensions which may include suspending agents and thickening agents.Theformulations may be presented in unit-dose or multi-dose containers,for example sealed ampules and vials including those suitable fordisposal after use, and may be stored in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier,such as water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Preferred unit-dose formulations are those that contain a daily dose orunit, daily sub-dose or appropriate fractional dose or sub-dose, of theadministered ingredient. Formulations comprising the compounds of thisinvention may include other agents conventional in the art pertaining tothe type of formulation in question. For example, formulations suitablefor oral administration may include flavoring agents, or coatings tofacilitate swallowing or to mask an unpleasant taste if a flavoring isnotused or is not completely effective. This invention covers thecompounds listed above which are 1-phenylalkanecarboxylic acidderivatives showing useful and effective anticonvulsant orneuroprotective activity in mammalsin the form of their free bases orappropriate salts, such as hydrochlorides, oxalates, tartrates,fumarates, etc., by standard pharmacological testing.

Effective methods of synthesizing novel compounds of the invention willbe described in relation to the reaction schemes and synthetic examplesset forth below.

SYNTHESIS

For brevity in the following discussion, chemical compounds which appearherein will be identified by reference numerals which will applyconsistently to their respective corresponding species throughout thereaction scheme diagrams, examples, etc. that follow. The numeralscorrespond to compounds as indicated in the following table, using thebasic reference structure defined above. Other compounds of theinvention for which synthesis is not specifically described in a workingexample maybe prepared by following the techniques described in theliterature cited herein and the techniques of the examples, using theexamples and the reaction schemes as guidance. All cited literature isincorporated by reference. Scheme I illustrates the synthetic proceduresdescribed in detail in Examples 1 and 2. Scheme II corresponds to thesynthetic chemistry of Example 3.

Chemistry

Melting points were determined using a Thomas-Hoover capillary meltingpoint apparatus and are uncorrected. ¹ H NMR spectra were obtained usingeither a Bruker AC 300 MHz or a Varian XL 300 MHz NMR spectrometer, withtrimethylsilane as the internal standard with both apparatuses. IRspectra were determined with a Nicolet Model 105 IR spectrometer usingeither potassium bromide pellets or chloroform cells. EIMS and CIMS(chemical inonization-NH₃) were obtained on a Finnegan 1015 massspectrometer. Flash column chromatography (silica gel, grade 60, 230-400mesh, Aldrich Chemical Company, Milwaukee, Wis.) was used forpurification. Product purity was tested by thin layer chromatography(silica gel GF, Analtech, DE); the solvent system used was CHCl₃ :CH₃OH:NH₄ OH (90:10:1) unless otherwise noted. Elemental analyses wereperformed by Spang Micro Analytical Laboratory, Eagle Harbor, Mich. Allnew compounds exhibited satisfactory mircroanalyses for C, H, and Nwithin 0.4% of theoretical values and/or mass, NMR and IR spectral dataconsistent with the structures assigned.

                  TABLE 1                                                         ______________________________________                                        Reference                                                                     Numeral     n             X                                                   ______________________________________                                        1           3             --CO.sub.2 --                                       2           3             --CH.sub.2 --O--                                    3           4             --CH.sub.2 --O--                                    4           4             --CO.sub.2 --                                       ______________________________________                                    

EXAMPLE 10-[2-(2-Diethylaminoethoxy)-ethyl]-1-phenyl-1-cyclopentanemethanol (2)

Step A

Methyl-1-phenyl-1-cyclopentanecarboxylate

A solution of 1-phenyl-1-cyclopentanecarboxylic acid (2.00 g, 10.51mmol) in 30 mL methanol saturated with HCl was stirred at reflux for twohours. The reaction mixture was allowed to cool and the solvent wasevaporated. The residue was dissolved in 50 mL dichloromethane andwashed with 2N sodium hydroxide (3×25 mL). The organic layer was washedwith water (2×25 mL) and dried (Na₂ SO₄). Evaporation of the solventgave 1.89 g (88%) of methyl-1-phenyl-1-cyclopentanecarboxylate as a paleyellow liquid and was used in the next step without furtherpurification. CIMS 205 m/z (M+1).

Step B

1-Phenylcyclopentanemethanol

A solution of the product of Step A (3.00 g, 14.71 mmol) in 10 mL THFwas added dropwise to a suspension of LiAlH₄ (1.25 g, 33.09 mmol) in 25mL dry THF. The reaction mixture was stirred at reflux for three hours.The excess LiAlH₄ was destroyed following the method described inReagents for Organic Synthesis, Vol 1 [1967] p. 584 (J. Wiley & Son), byquenching the cooled reaction mixture with the addition of 1.25 mLwater, followed by the addition of 1.25 mL 154 sodium hydroxide (w/v),followed by the addition of 3.75 mL water. The resulting aluminum saltswere separated by filtration and washed with water (5×1 mL). The productwas extracted with ether (3×25 mL) and dried (Na₂ SO₄). Evaporation ofthe solvent gave 2.07 g (88%) of 1-phenylcyclopentanemethanol as a whitesolid, mp 41°-44° C.(the literature value of mp, J. Org. Chem. 27:3434(1962), is 43°-44° C.).

Step C

2-(2-Diethylaminoethoxy)-ethyl Chloride

A modification of the procedure described in J. Am. Chem. Soc. 76:3163(1954) was used to obtain this compound, beginning with the dropwiseaddition of thionyl chloride (17.02 mL, 233.42 mmol) to a solution of2-(2-di-ethylaminoethoxy)-ethanol in benzene (100 mL). The reactionmixture was stirred at reflux for 1.5 hours and the volatiles wereremovedunder diminished pressure. The oily residue crystallized inether, was nearly homogeneous by TLC, and was used without furtherpurification. The HCl salt obtained in this reaction was veryhygroscopic. Attempts at purification of the free base via distillationresulted in decomposition. CIMS 180 m/z (M+1), 183 m/z (M+3).

Step D

0-[2-(2-Diethylaminoethoxy)-ethyl]-1-phenyl-1-cyclopentanemethanol (2)

A solution of the product of Step B (2.21 g, 12.56 mmol) in dry DMF (10mL)was carefully added to NaOH (1.00 g, 25.12 mmol, 60% suspension inmineral oil) previously washed with petroleum ether (4×5 mL), under anatmosphere of argon, at 0° C. After the addition was complete thereaction mixture was stirred at room temperature for 30 minutes. The HClsalt of Step C (13.56 g, 62.78 mmol) was dissolved in 10% sodiumhydroxide(50 mL) and the free base was extracted with chloroform (5×25mL), dried (Na₂ SO₄) and the solvent was evaporated under diminishedpressure. The dark orange residue was added dropwise to the reactionmixture. The addition funnel was washed with DMF (5 mL) and the reactionmixture was stirred overnight at 95°-100° C. The resulting mixture wascarefully quenched with water (5 mL) and the product was extracted withether (2×25 mL). The organic layer was washed with 1NHCl (3×25 mL). Theether layer was dried (Na₂ SO₄) and evaporated, affording unreactedproduct of Step B starting material (1.40 g, 7.95 mmol). The combinedaqueous solution was washed with ether (2×25 mL) basified to pH 9 withNH₄ OH, extracted with chloroform (3×25 mL) and dried (Na₂ SO₄). Removalof the solvent in vacuo afforded Compound 2 as a pale yellow oil (0.74g, 50% yield based on recovered starting material). The oxalatehemihydrate salt was obtained by dissolving the free base (0.74 g, 2.31mmol) in a minimal volume of methanol and adding it to a solution ofoxalic acid (0.21 g, 2.31 mmol) in hot methanol. The solvent wasevaporated and the salt recrystallized from isopropanol/ether, mp67°-69° C. ¹ H NMR (D₂ O) delta 1.22 (t, J=7.3 Hz, 6H), 1.68-1.72 (m,4H), 1.88-1.90 (m, 4H), 3.10-3.21 (m, 6H), 3.52-3.61 (m, 6H), 3.66 (s,2H), 7.27-7.46 (m, 5H); CIMS 319 m/z (M+1). Anal. (C₂₂ H₃₅ NO₆.1/2H₂ O)C, H, N.

EXAMPLE 20-[2-(2-Diethylaminoethoxy)-ethyl]-1-phenyl-1-cyclohexanemethanol (3)

Step A

1-Phenyl-1-cyclohexanecarboxylic Acid

A modification of the procedure for hydrolyzing nitriles described inCan. J. Chem. 40:1909 (1962) was used to obtain this compound. Asolution of 1-phenyl-1-cyclohexanecarbonitrile (20.0 g, 108 mmol) in 80mL 48% HBr wasstirred at reflux for four days. The solution was basifiedwith 10% sodium hydroxide (w/v) to pH 8-9, then washed with ether (3×25mL). The aqueous layer was acidified with 1N HCl to pH of 2-3, then theproduct wasextracted with ether (4×25 mL), giving 15.9 g of1-phenyl-1-cyclohexanecarboxylic acid (72%), mp 118°-121° C.(comparedwith the literature value, J. Am. Chem. Soc. 56:715 (1934), of 121° C.).

Step B

Methyl-1-phenyl-1-cyclohexanecarboxylate

This compound was prepared (1.91 g, 8.76 mmol, 89%) from the product ofStep A (2.00 g, 9.8 mmol) following the procedure for synthesis ofmethyl-1-cyclopentanecarboxylate as set forth in Step A, Example 1. Theproduct of this step was homogeneous by TLC (ether:C₂ Cl₂, 2:1) and usedin the next step without further purification. CIMS 219 m/z (M+1).

Step C

1-Phenylcyclohexanemethanol

This compound was prepared (1.02 g, 5.43 mmol, 62%) from the product ofStep B (1.91 g, 8.76 mmol) using LiAlH₄ (0.75 g, 37.95 mmol) accordingto the procedure for synthesizing 1-phenylcyclopentanemethanol set forthin Step B, Example 1, with the exception that this compound precipitatedout of solution following the steps of: (a) destroying the excesshydride; (b) separating the aluminum salts by filtration; and (c)washing with water (3×4 mL in this Example). Filtration of theprecipitate gave 1-phenylcyclohexanemethanol as a white solid, mp63°-64° C. (compared with reported value, J. Org. Chem. 27:3434 (1962),of 63°-64° C.).

Step D

0-[2-(2-Diethylaminoethoxy)-ethyl]-1-phenyl-1-cyclohexanemethanol (3)

Compound 3 was prepared (1.0 g, 3.0 mmol, 39%) from the product of StepC (1.45 g, 7.63 mmol) according to the procedure for synthesizingcompound 2set forth in Step D, Example 1. The product 3 was purified byflash column chromatography (CHCl₃ :CH₃ OH:NH₄ OH, 90:10:1). Theoxalatesalt was obtained by dissolving the free base (0.34 g, 1.01 mmol)in a minimal volume of hot methanol and adding it to a solution of 0.09g oxalic acid (8.75 mmol) in hot methanol. The solvent was evaporatedand the salt recrystallized from isopropanol/ether, mp 84°-85° C. ¹ HNMR (D₂ O) delta 1.24 (t, J=7.3 Hz, 6H), 1.32-1.66 (m, 8H), 2.08-2.13(m, 2H), 3.12-3.23 (m, 6H), 3.45-3.62 (m, 8H), 7.29-7.53 (m, 5H); CIMS334 m/z (M+1). Anal. (C₂₃ H₃₇ NO₆) C, H, N.

EXAMPLE 3 2-(2-Diethylaminoethoxy)-ethyl-1-phenyl-1-cyclohexanecarboxylate (4)

A solution of 1-phenyl-1-cyclohexanecarboxylic acid (1.02 g, 5 mmol) and2.5 mL thionyl chloride in 25 mL toluene was stirred at reflux for twohours under an atmosphere of argon. The solvent was evaporated underdiminished pressure and the acid chloride(1-phenyl-1-cyclohexanecarboxyl chloride) was dissolved in 20 mLtoluene. A solution of diethylaminoethoxyethanol (0.85 mL, 5 mmol) andtriethylamine (0.75 mL) was added dropwise tothe acid chloride solution.The mixture was stirred at reflux for three hours and then was allowedto stand at room temperature overnight. The triethylamine HCl formed inthe reaction was separated by filtration and the filtrate was washedwith toluene (3×1 mL). The solvent was evaporated and the residue wasdissolved in 25 mL 20% NH₄ OH. The product was extracted with chloroform(3×25 mL) and the combined organic fraction was washed with water (2×25mL) and dried (Na₂SO₄). The solvent was evaporated, affording compound 4as a pale yellow oil (1.72 g, 99%). The citrate salt was prepared bydissolving the free base (0.50 g, 1.44 mmol) in a minimal volume of hotmethanol and adding it to a solution of 0.28 g citric acid (1.44 mmol)in hot methanol.Addition of anhydrous ether resulted in the crystallinefumarate salt, which was recrystallized from methanol/ether, mp 86°-87°C. ¹ H NMR (D₂ O) delta 1.20 (t, J=7.2 Hz, 6H), 1.41-1.85 (m, 8H),2.38-2.41 (m, 2H), 3.07-3.14 (m, 6H), 3.57-3.70 (m, 4H), 4.28 (t, J=4Hz, 2H), 7.33-7.50 (m, 5H); CIMS 348 m/z (M+1). Anal. (C₂₇ H₄₁ NO₁₀) C,H, N.

The utility of the compounds of this invention, described above, forcontrolling seizures and convulsions has been established throughstandardlaboratory testing. The testing protocol and the resultsobtained will be described in the following section.

UTILITY

The anticonvulsant activity of the present compounds was assessed by themethod of inducing maximal electroshock seizures (MES) in rats using thestandard testing protocol conditions hereinafter described:

Animals. Male Sprague-Dawley rates weighing 225-275 g obtained fromZivic Miller Laboratories, Alison Park, Pa., were used for allexperiments. Upondelivery the animals were kept in individual penshoused in a temperature controlled laboratory. A standard 12-hourlight-dark cycle was maintained.The animals were given food and water adlibitum. The animals were randomlyassigned as control group animals ordrug-treated animals.

Maximal electroshock seizures (MES) assay. Supramaximal (tonic handlimbextension) seizures were induced in test rates by means of an electricshock apparatus. A current of 60 Hz and 50 mA was deliveredtransauricularly through miniature alligator clips attached to the pinnaof each ear for 2.0 seconds. The shock parameters used in the studieshavebeen shown to induce MES, and not threshold seizures. In general,MES causes a generalized convulsion characterized by an initial tonicforelimbextension (TFE) progressing immediately to tonic hindlimbextension (THE) followed by clonic jerking. The presence or absence ofTHE was recorded for each MES convulsion.

Experimental protocol. Two groups of animals with n=10 for each groupwere tested under the conditions described above. Compounds wereadministered to each test animal by a single subcutaneous injection.There were no signs of overt sedation, ataxia or motor impairment at anytime during theMES assay after drug injection.

Drug-treated animals received a single subcutaneous injection ofcompounds 2, 3 and 4 of this invention in varying doses, as specifiedbelow. Carbetapentane (compound 1) was administered in doses rangingfrom 6.25-50.0 mg/kg. Drug-treated animals were also tested for reactionto diphenyhydantoin (DPH). Active ingredients were diluted in deionizedwater. In all cases, control animals received respective vehicletreatments (1 mL/kg, sc). All the animals tested, whether in thedrug-treated or control groups, were naive to drug and seizure, and eachanimal was used only once. The dose-response experiments were done atthe interval of 30 minutes after injection, the reported time of peakanticonvulsant response for carbetapentane. FIG. 1 plots theanticonvulsant activity of compounds of the invention is comparison withcarbetapentane. The utility data in FIG. 1 is presented in a semilogplot of the percentage of seizure protection versus the indicateddosages of the given anticonvulsant compounds. In the figure, thereference numeral 1signifies carbetapentane; 2 signifies0-[2-(2-diethylaminoethoxy) ethyl]-1phenyl-1-cyclopentanemethanol; 3represents0-[2-(2-diethylaminoethoxy)-ethyl]-1-phenyl-1-cyclohexanemethanol; and 4denotes 2-(2-diethylaminoethoxy)-ethyl-1-phenyl-1-cyclohexanecarboxylate.

The anticonvulsant activity of compounds of the invention in comparisonwith carbetapentane and diphenylhydantoin as determined by the MES assayexperimental protocol described above is summarized in Table 2.

                  TABLE 2                                                         ______________________________________                                                   Anticonvulsant                                                     Compound     ED.sub.50 (umol/kg)                                                                        mg/kg (s.c.)                                        ______________________________________                                        DPH          30            8                                                  1            48           25                                                  2            16            7                                                  3            86           37                                                  4            173          93                                                  ______________________________________                                    

The invention has been described and illustrated with respect to certainspecific embodiments. Without departing from the spirit and scope ofthis invention, one of ordinary skill can make various changes andmodifications to the invention to adapt it to various usages andconditions. As such, these changes and modifications are properly,equitably, and intended to be, within the full range of equivalence ofthefollowing claims. ##STR3##

What is claimed is:
 1. A compound having the formula:wherein X is --CH₂O--, [--C(═O)O--, ] --C(═O)NH, CH₂ NH, or --CH₂ N(C₂ H₅), and n is aninteger between 1-5; or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1 contained in a liquid injectable dosage form. 3.The compound of claim 1 contained in a liquid oral dosage form.
 4. Thecompound of claim 1 contained in a solid oral dosage form.
 5. Thecompound of claim 1 wherein X is --CH₂ O-- and n is 3, which is0-[2-(2-diethylaminoethoxy)-ethyl]-1phenyl-1-cyclopentanemethanol. 6.The compound of claim 5 contained in a liquid injectable dosage form. 7.The compound of claim 5 contained in a liquid oral dosage form.
 8. Thecompound of claim 5 contained in a solid oral dosage form.
 9. Thecompound of claim 1 wherein X is --CH₂ O-- and n is 4, which is0-[2-(2-diethylaminoethoxy)-ethyl]-1phenyl-1-cyclohexanemethanol. 10.The compound of claim 9 contained in a liquid injectable dosage form.11. The compound of claim 9 contained in a liquid oral dosage form. 12.The compound of claim 9 contained in a solid oral dosage form.
 13. Amethod of treating a mammal for convulsions which comprisesadministering to said mammal an effective anticonvulsant orneuroprotective amount of a compound having the formula: ##STR4##wherein X is --CH₂ O--, --C(═O)O--, --C(═O)NH, CH₂ NH, or --CH₂ N(C₂H₅), and n is an integer between 1-5, provided that when X is --C(═O)O--then n may not be 3; or a pharmaceutically acceptable salt thereof. 14.The method of claim 13 wherein the anticonvulsant or neuroprotectivecompound administered is0-[2-(2-diethylaminoethoxy)-ethyl]-1-phenyl-1-cyclopentanemethanol. 15.The method of claim 13 wherein the anticonvulsant or neuroprotectivecompound administered is0-[2-(2-diethylaminoethoxy)-ethyl]-1-phenyl-1-cyclohexanemethanol, 16.The method of claim 13 wherein the anticonvulsant or neuroprotectivecompound administered is2-(2-diethylaminoethoxy)-ethyl-1-phenyl-1-cyclohexane carboxylate. 17.The method of claim 13 wherein the amount of the compound to beadministered is 1,000 mg or less of active ingredient.